Long‐term outcomes of rapid antiretroviral NNRTI‐based initiation among Thai youth living with HIV: a national registry database study

Introduction The Thai National AIDS programme (NAP) treatment guidelines have recommended rapid antiretroviral therapy (ART) initiation, regardless of CD4 count since 2014. We assessed treatment outcomes among youth living with HIV (YLHIV), initiating first‐line ART and assessed the association between virological failure (VF) and timing of ART initiation. Methods We retrospectively reviewed data for YLHIV aged 15–24 years, initiating non‐nucleoside reverse transcriptase inhibitor‐based ART from 2014 to 2019, through the NAP database. We classified the timing of ART into three groups based on duration from HIV‐positive diagnosis or system registration to ART initiation: (1) <1 month (rapid ART); (2) 1–3 months (intermediate ART); and (3) >3 months (delayed ART). VF was defined as viral load (VL) ≥ 1000 copies/ml after at least 6 months of first‐line ART. Factors associated with VF were analysed using generalized estimating equations. Results Of 19,825 YLHIV who started ART, 78% were male. Median (interquartile range, IQR) age was 21 (20–23) years and CD4 count was 338 (187–498) cells/mm3. After registration, 12,216 (62%) started rapid ART, 4272 (22%) intermediate ART and 3337 (17%) delayed ART. The proportion of YLHIV starting ART <30 days significantly increased from 43% to 57% from 2014–2016 to 2017–2019 (p < 0.001). The median duration of first‐line therapy was 2 (IQR 1–3) years and 89% started with efavirenz‐based regimens. Attrition outcomes showed that 325 (2%) died (0.73 [95% CI 0.65–0.81] per 100 person‐years [PY]) and 1762 (9%) were loss to follow‐up (3.96 [95% CI 3.78–4.15] per 100 PY). Of 17,512 (88%) who had VL checked from 6 to 12 months after starting treatment, 80% achieved VL <200 copies/ml. Overall, 2512 experienced VF 5.87 (95% CI 5.65–6.11) per 100 PY). In a multivariate model, the adjusted incidence rate ratio for VF was 1.47 (95% CI 1.33–1.63, p < 0.001) in the delayed ART group and 1.14 (95% CI 1.03–1.25, p< 0.001) in the intermediate ART group, compared to YLHIV in the rapid ART group. Conclusions Rapid ART initiation after diagnosis was associated with significantly reduced risks of VF and death in YLHIV, supporting the implementation of rapid ART for optimizing health outcomes.


I N T R O D U C T I O N
In 2015, the World Health Organization (WHO) recommended commencing antiretroviral therapy (ART) at any CD4 count [1]. As countries have adopted this "treat all" policy, the time to initiate ART after an HIV diagnosis has decreased, and the proportion of people living with HIV (PLHIV) who rapidly initiate ART rapidly has increased [2][3][4]. Several studies reported that rapid ART initiation is associated with reduced morbidity and mortality, and a higher probability virological suppression and retention in care [5][6][7][8]. WHO subsequently recommended initiating treatment within 7 days of a confirmed HIV diagnosis, and same-day initiation when feasible [9]. Adoption of treat all policies has led to increasing rates of same-day ART, or rapid ART initiation within 30 days of diagnosis [2,5,6,10]. However, even in these contexts, treatment outcomes may still fall short of WHO 95:95:95 goals. A same-day ART implementation science project in adults in Bangkok in 2017/2018 demonstrated retention rates of 75.3%, only 53.4% received viral load (VL) testing, and only 49.3% of all participants initiating ART achieved viral suppression within the first year [8]. In the era of rapid ART initiation, the largest group of new HIV diagnoses are youth who acquired HIV behaviourally, particularly young men who have sex with men [11][12][13]. Before "treat all" policies came into effect, in many different settings, these youth had loss to follow-up (LTFU) rates ranging from 11% to 48% prior ART initiation. These LTFU rates were substantially higher than rates in adults, which ranged from 10.8% to 38% [14][15][16][17][18].
Other studies have shown reductions in LTFU among those >18 years after the implementation of rapid ART policies, and youth living with HIV (YLHIV) aged between 15 and 24 years were at higher risk of attrition compared to adults living with HIV [19][20][21][22][23][24].
In Thailand, PLHIV are offered free HIV care and treatment through the National AIDS programme (NAP) [25] and national treatment guidelines are regularly updated based on the best available evidence, to optimize treatment outcomes [26]. In a recent study of treat all policy on rapid ART initiation in Thai YLHIV, the proportion initiating ART within 1 month after registration increased from 27% in the year 2014 to 52% in 2019, and ART initiation within 6 months after registration increased from 47% to 74% [27]. However, long-term outcomes data in youth by timing of ART initiation in real-world settings are limited. We aimed to assess long-term treatment outcomes among YLHIV, initiating firstline, non-nucleoside reverse transcriptase inhibitor (NNRTI)based ART in the NAP, and assessed the association between virological failure (VF) and timing of ART initiation. We also determined factors associated with switches to second-line regimens.

The NAP database
The NAP programme is the main health insurance programme in Thailand for delivering treatment and care to PLHIV [25,27]. Hospitals and clinical sites enter laboratory results, clinical information and ART dispensing records into the database system at patient registration and subsequent visits; this information is used to reimburse hospitals for laboratory tests and medications provided. CD4 tests are conducted every 6 months, and HIV-RNA is measured 6 months after starting ART, and annually thereafter. ART is provided based on National HIV treatment guidelines [26]. The database is linked with the National Death Registry, and vital status is updated daily.

Study population
This retrospective cohort study included YLHIV aged 15-24 years, who initiated treatment with National Guideline recommended NNRTI-based ART between January 2014 and May 2019. Follow-up data were available until May 2020. YLHIV were eligible for inclusion if they had at least one VL test after ART initiation during follow-up for treatment monitoring. We allowed at least a year of follow-up for all patients to establish this treatment outcome. We assumed the majority of YLHIV acquired HIV behaviourally, since HIV transmission mode is not recorded in the database; our assumption reflects the situation in Thailand during the study period [12]. Patients who started with nucleoside reverse-transcriptase inhibitors only or protease inhibitors (PIs) were excluded; guidelines recommend PI-based ART for pregnant women, but we were unable to ascertain pregnancy status [26]. Integrase strand transfer inhibitor-based regimens were not recommended at the time of the study, and therefore, not available for use in the NAP. We excluded patients who initiated ART before NAP enrolment, because no clinical information for these patients was available at ART initiation. Only 5% of PLHIV started treatment in facilities outside the NAP [25]. Patients taking ART <6 months were also excluded since no VL tests are done during this period. This study was approved by the Institutional Review Board of the Institute for Development of Human Research Protection, Ministry of Public Health, Thailand. A waiver of consent was granted for this data analysis. The NAP database was de-identified by the National Health Security Office before analysis.

Definitions and outcomes
We classified YLHIV into three groups based on duration from registration (HIV-positive test) to ART initiation following treatment guidelines for 2014-2019. Those starting ART <1 month from registration were classified as rapid ART.
Intermediate ART was defined as starting ART 1-3 months after registration; those starting >3 months were defined as delayed ART. Periods of starting ART were classified into two periods (2014-2016 and 2017-2019) to assess trends in accessing rapid ART. NNRTI-based treatment included NNR-TIs available in Thailand, namely efavirenz (EFV), nevirapine (NVP) or rilpivirine (RPV). VL within the first year was defined as VL measurements from 6 to 12 months after ART initiation. VF was defined as VL ≥ 1000 copies/ml during followup. Follow-up time on first-line therapy was censored on the date of the last visit or the date of switching to secondline ART for those who switched. Patients who died or were LTFU were censored at their last visit. Switching to secondline ART was defined as changing from an NNRTI-to PIbased regimen, with confirmed VF after at least 6 months of treatment. Mortality was confirmed in the death registry. LTFU was defined as not attending clinic visits for ≥ 12 months, irrespective of whether or not patients later returned to NAP after ART initiation. Pre-ART CD4 count was defined as the closest result within a window 12 months before, or up to 1 month after the date of ART initiation. Geographic regions of Thailand were classified according to classifications used by government organizations. History of opportunistic infections at ART initiation was entered in the database as "yes or no."

Statistical analysis
Baseline demographic, disease and treatment information were summarized by ART initiation group. Comparisons of categorical characteristics between ART groups were performed using Pearson's Chi-square test and continuous characteristics were compared using a Kruskal-Wallis test. Mortality, LTFU, VF and second-line ART switch rates were calculated per 100 person-years of follow-up (PY). Associations between timing of ART initiation and VF were analysed using generalized estimating equations (GEE) model with a Poisson distribution, log link function and exchangeable correlation matrix. Competing risk models [28] were used to calculate the cumulative incidence of second-line ART switch, and sub-distribution hazard ratios (SHRs) quantitated associations between patient characteristics and the second-line switch. LTFU and death were considered competing events.
Covariates assessed in both GEE and competing risk models included age, gender, ART initiation group, first regimen, pre-ART CD4, country region, year of starting ART and opportunistic infections. Variables with p < 0.10 in univariable screening were adjusted for in multivariable models. Statistical significance was identified using a two-sided p value less than 0.05. Statistical analysis was performed with SAS version 9.4 (SAS Institute Inc, Cary, NC) and Stata version 16 (StataCorp, College Station, TX).

R E S U LT S
A total of 21,968 youth started ART through the NAP from 2014 to 2019. We excluded 1320 (6%) youth who initiated PI-based regimens, and 823 (4%) who were not eligible for VL testing because the duration on ART was <6 months. This resulted in an analysis population of 19,825 youth.  32% >7 days to 1 month). The intermediate and delayed ART initiation groups comprised 4272 (22%) and 3337 (17%) YLHIV, respectively. The majority of patients were male; the median age at ART initiation was 21 (IQR 20-23) years. Five percent had an opportunistic infection at baseline; the median pre-ART CD4 count was 338 (IQR 187-498) cells/mm 3 . Most YLHIV started with EFV-based regimens (89%), followed by NVP-(10%) and the smallest proportion started with RPVbased ART (1%) which only became available in later years of the study period. The majority of YLHIV (25%) were from the Northeastern region. Figure 1 shows the percentage of YLHIV starting ART by timing relative to diagnosis and region. YLHIV in Bangkok had the highest percentage starting rapid ART (66%), whereas the Western region had the highest percentages in the intermediate ART (34%) and delayed ART groups (21%). The highest percentage of YLHIV who started same-day ART (28%) were in Bangkok.

Patient characteristics
For the ART initiation group, YLHIV who initiated ART within 1 month from HIV diagnosis increased from 43% in 2014-2016 to 57% in 2017-2019, with a median duration from registration to initiation of 2 (IQR 1-3) days. Those initiating same-day ART and starting ART within 7 days both increased by 3% in the second study period (15-18%, and 11-14%, respectively). Median pre-ART CD4 count in YLHIV in rapid and delayed ART groups was higher versus the intermediate ART group

Mortality and LTFU outcomes
Outcomes after ART initiation are shown in Figure 2.

Factors associated with second-line ART regimen
In the adjusted competing risk regression model (  (Figure 3b). Regimen switch rates were 53% higher in men (aSHR 1.53, 95% CI 1.32-1.77) than in women. Patients aged <20 years (aSHR 2.30 95% CI 1.92-2.76) were more likely to switch to second-line ART compared to those aged ≥ 20 years. A lower pre-ART CD4 count <200 cells/mm 3 (aSHR 5.40, 95% CI 4.49-6.50) and pre-ART CD4 count 200 to <350 cells/mm 3 (aSHR 1.86, 95% CI 1.50-2.31) were at a higher risk of switching to secondline regimens than those with CD4 counts ≥ 350 cells/mm 3 . YLHIV with opportunistic infections at baseline had a higher chance of switching to second-line ART compared to those who did not. Regions and first regimen were also associated with the second-line switch.
Sensitivity analyses included only YLHIV (73%, n = 14,554) with an ascertained date of HIV diagnosis (Tables S1-S3). Rapid, intermediate and delayed ART initiation groups comprised 8945 (62%), 3236 (22%) and 2373 (16%, p<0.001) YLHIV, respectively. The median duration from HIV diagnosis to ART initiation was 22  days. Outcomes after ART initiation were consistent with the main study outcomes, with an increased risk of VF second-line ART switch in the intermediate and delayed ART, compared to the rapid ART group ( Figure S1).

D I S C U S S I O N
This is the first study assessing long-term treatment outcomes among YLHIV in the Thai NAP, by timing of ART initiation after the "treat at any CD4 count" policy was adopted. Mortality of YLHIV starting rapid ART reduced with time, while the LTFU rates were similar among ART initiation groups. Viral suppression in the first year of treatment was also significantly higher among YLHIV in the rapid initiation group. Moreover, YLHIV starting rapid ART were less likely to have VF or switch to second-ART, compared with those starting immediate or delayed ART. Similar results were found in sensitivity analyses which excluded those in whom the exact date of HIV diagnosis could not be ascertained. These findings are likely effects of guideline changes with rapid ART initiation leading to better long-term outcomes for YLHIV starting first-line therapy. Moreover, uptake of rapid ART increased over time, as did pre-ART CD4 in this group, whereas pre-ART CD4 in the intermediate and delayed ART groups changed only slightly, perhaps partly because opportunistic infections as tuberculosis needed to be treated for 2-8 weeks before ART initiation [26].
Increases in rapid ART initiation observed after the implementation of a treat all policy in this current study are similar to a report from sub-Saharan Africa, where a treat all policy adoption also increased the numbers of young adolescents accessing ART rapidly [4,10]. Policy changes regarding rapid ART initiation led to decreased mortality rates and increased retention in care, similar to those in our study [29,30]. YLHIV starting rapid ART had the lowest mortality rates, consistent with results from randomized control trials and cohort studies [27,31]. Rapid ART initiation also accelerated viral suppression rates. Viral suppression at VL < 200 copies/ml increased from 75% in 2014-2018 to 82% in our second study period. This is consistent with studies from Egypt, Haiti and Taiwan where those who started rapid ART had increased rates of viral suppression [7,[31][32][33]. Socio-economic and psychosocial factors can influence the timing of ART initiation and treatment outcomes. Previous studies from South Africa reported significant associations between timing of ART initiation and factors including level of facility, number of people in the household and having a partner [24,34,35].
Annual VL testing after ART initiation is offered for monitoring treatment in Thai YLHIV. Our analysis showed that VF rates were lowest in the rapid treatment group and highest in those initiating ART between 1-3 months, and >3 months after diagnosis. A study from 26 countries demonstrated that regular VL monitoring in adolescents has increased in low/lower-middle-income countries after the adoption of treat all policies, and is critical for the early detection of treatment failure [36][37][38]. Furthermore, YLHIV who started ART rapidly had a lower risk of switching to second-line ART compared to other ART initiation groups. Ninety percent of switches to second-line ART in our study had confirmed VF, with a median time to switch of 1.5 years. Our finding indicates a lower cumulative incidence of switching to second-line ART after 3 years of rapid ART initiation (5.3%) compared to an individual patient data meta-analysis study from Thailand (8%) and Europe (14-16%) before the era of treating at any CD4 levels [39]. Moreover, the proportion with confirmed VF with switching to second-line ART in our study was also higher than adults living with HIV where rates ranged from 43% to 66% in studies from Eswatini, Uganda and Lesotho [40][41][42]. However, YLHIV aged < 20 years were at higher risk of switching to second-line ART, compared to those aged older than 20 years [42,43]. This finding suggests the scale-up of rapid ART initiation in YLHIV would probably increase the rate of viral suppression and immediately switching to secondline ART after detecting VF. A strength of this study is the description of long-term outcomes after rapid ART initiation in Thai YLHIV in a large National database, and the first study to assess longterm treatment outcomes in Asian YLHIV by timing of ART initiation. It reflects real-life practice and outcomes in a lowmiddle income country in response to National treatment guideline changes, and demonstrates progress towards achieving the UNAIDS 95:95:95 goals. There are a number of limitations of this study. First, we defined the date of registration with NAP as a surrogate for the date of HIV diagnosis, which could create bias by shortening the time from HIV diagnosis to ART initiation, as some patients (37%) may have been diagnosed at private clinics and re-tested at NAP registration. However, excluding these unknown diagnosis dates in a sensitivity analysis did not change the main study findings (Tables  S1-S3). Second, the NAP database does not record details about socio-economic and psychosocial factors, such as caregiver status, education, occupation, income and behavioural risks, so we could not examine the effects of these factors which might also influence access to rapid ART, as well as treatment outcomes. Third, 5% of YLHIV had missing pre-ART CD4 counts, most likely because of delayed data entry or human error; however, we classified participants in this group as unknown CD4. Fourth, due to the observational nature of our study, the possibility of unobserved confounding influencing the relationship between ART initiation and study outcomes cannot be discounted. Last, this study was conducted from 2014 to 2019, prior to dolutegravir (DTG) implementation. It is, therefore, likely that rates of VF described in this study may continue to fall in the future, compared to YLHIV who initiated NNRTI-based regimens in this study.

C O N C L U S I O N S
The proportion of YLHIV starting ART <30 days after HIV diagnosis significantly increased from 2014 to 2019 in the Thai NAP. These rapid ART initiators had a significantly lower risk of VF compared to those where initiation was delayed to 1-3, or >3 months. However, despite increasing rapid ART rates with predominantly EFV-based regimens, VL suppression was below the 95% UNAIDS target. DTG rollout should be expedited to achieve better programme outcomes.

C O M P E T I N G I N T E R E S T S
KR has received the Senior Research Scholar from Thailand Research Fund (TRF). And he received honoraria or consultation fees from Merck, Roche, Jensen-Cilag, Tibotec, Mylan and GPO (Governmental pharmaceutical organization, Thailand). He also has participated in a company-sponsored speaker's bureau from Abbott, Gilead, Bristol-Myers Squibb, Merck, Roche, Jensen-Cilag, GlaxoSmithKline and GPO (Governmental pharmaceutical organization). TP received a clinical research grant from ViiV and MSD. ST was funded as a CIPHER grantee from the International AIDS Society, 2018-2020.

A U T H O R S ' C O N T R I B U T I O N S
ST, SJK, KR and TP created the study concept and study design. ST, SJK, PK and KR were responsible for data collection or oversaw programme implementation. ST conducted the analysis. SJK, KR and TP advised on the analysis. ST, SJK, PK, KR and TP interpreted the data. ST drafted the manuscript. All authors critically reviewed the manuscript and approved the manuscript for submission.

A C K N O W L E D G E M E N T S
The dataset was provided by the National Health Security Office (NHSO) and the Ministry of Health in Thailand. The content of this publication is solely the responsibility of the authors. The CIPHER grant was funded by the International AIDS Society, 2018-2020. This research was supported by HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand

F U N D I N G
The CIPHER grant was funded by the International AIDS Society, 2018-2020. HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand. International SciKU Branding (ISB) is funded by the Faculty of Science, Kasetsart University.

D I S C L A I M E R
The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the governments or institutions mentioned above. Data were presented as an oral presentation in part at the International Workshop on HIV Pediatrics 2021. Virtual conference, 16/07/2021-17/07/2021.

D ATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

S U P P O R T I N G I N F O R M AT I O N
Additional information may be found under the Supporting Information tab for this article: Table S1: Characteristics of youth living with HIV at ART initiation stratified by time of ART initiation which limited to YLHIV with documented date of HIV diagnosis (n=14,554). Table S2: Incidence rate ratios for factors associated with virological failure (plasma HIV RNA ≥ 1,000 copies/mL) after first-line ART initiation (n=14,554). Table S3: Univariable and multivariable associations with switching to second-line (PI-based) ART from a competing risks regression model (nd˜14,554). Figure S1: Study outcomes after ART initiation in youth living with HIV in the Thai National HIV Treatment program, by timing of ART initiation (n=14,554).